Flurbiprofen is a propionic acid derivative and is a known NSAID (non-steroidal anti-inflammatory drug) with analgesic and anti-inflammatory activity. Its chemical structure is shown in the Formula 1.

The chemical name of flurbiprofen is 2-Fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid. It is used in musculoskeletal and joint disorders such as ankylosing spondylitis, osteoarthritis and rheumatoid arthritis, in soft-tissue disorders such as sprains and strains, for postoperative pain and mild to moderate pain including dysmenorrhea and migraine.
Flurbiprofen is also used as lozenges in the symptomatic relief of sore throat. Flurbiprofen sodium is used in eye drops to inhibit intra-operative miosis and to control postoperative inflammation of the anterior segment of the eye. Flurbiprofen axetil has been given in some countries by intravenous injection for severe pain.
For pain and inflammation, flurbiprofen is given in usual doses of 150 mg to 200 mg daily by mouth in divided doses, increased to 300 mg daily in acute or severe conditions if necessary (Sean C Sweetman, Martindale The Complete Drug Reference, thirty-fifth edition 2007, Vol. 1, pages 52 to 53).
Muscle relaxants are used in the management of musculoskeletal and neuromuscular disorders. There are two main types; centrally acting relaxants and directly acting relaxants.
Centrally acting relaxants generally have a selective action on the central nervous system (CNS) and are principally used for relieving painful muscle spasms or spasticity occurring in musculoskeletal and neuromuscular disorders. Their mechanism of action may be due to their CNS-depressant activity.
Tizanidine is an example for this group of muscle relaxants. Its chemical structure is shown in Formula 2.

Tizanidine is a α2-adrenergic agonist and acts mainly at spinal and supraspinal levels to inhibit excitatory interneurones. It is used for the symptomatic relief of spasticity associated with multiple sclerosis or with spinal cord injury or disease. It is also used in the symptomatic treatment of painful muscle spasm associated with musculoskeletal conditions (Sean C Sweetman, Martindale The Complete Drug Reference, thirty-fifth edition 2007, Vol. 1, page 1727).
Muscle relaxants also reduce muscle tone and are used in therapy for the treatment of muscle spasm and contractures.
Muscle spasm is one of the main factors responsible for chronic pain; it characterises several pathologies of the locomotor apparatus as well as inflammatory-rheumatic and degenerative orthopaedic pathologies; when it affects joints, they cause not only pain, but also rigidity, which reduces joint mobility and flexibility in the affected part. Muscle contractures also characterize several pathologies of the locomotor apparatus and are one of the main factors responsible for the persistence of the pain associated to these pathologies.
For these reasons the study of molecules endowed with muscle relaxant and antispasmodic properties still raises remarkable interest from the clinical point of view.
As it is known, colchicine is a pseudoalkaloid that has been widely used for a long time in therapy for the treatment of gout. The use of 3-demethyl-thiocolchicine glucoside, known as thiocolchicoside, is also widespread in therapy for treating contractures and inflammatory conditions that affect the muscular system (Ortopedia e traumatologia Oggi XII, n. 4, 1992).
Thiocolchicoside, has been claimed to possess GABA-mimetic and glycinergic actions, in other way we can say that thiocolchicoside is a gamma-aminobutiric acid receptor agonist. Its chemical structure is shown in Formula 3.

It has recently been shown that thiocolchicoside's activity can be ascribed to its ability of interacting with the strychnine-sensitive glycine receptors and therefore that compounds endowed with glycino-mimetic activity can be used in the rheumatologic-orthopedic field for their muscle relaxant properties.
The usual initial dose is 16 mg daily by mouth. It has also been given intramuscularly, in doses up to 8 mg daily, or applied as cream or ointment (Sean C Sweetman, Martindale The Complete Drug Reference, thirty-fifth edition 2007, Vol. 1, page 1738).
Muscle relaxants have been evaluated alone or in combination with conventional analgesics for the treatment of pain. Mixed and unpredictable results have been obtained in a pharmaceutical composition. But flurbiprofen has not previously been combined with an α-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist in a pharmaceutical composition for the treatment of inflammatory, pain and musculoskeletal diseases.
Tizanidine and/or Thiocolchicoside is a known muscle relaxant agents and sequentially they belong to the groups of α-2 adrenergic receptor agonists and a gamma-aminobutiric acid receptor agonists used in the treatment of painful muscle spasms or spasticity occurring in musculoskeletal and neuromuscular disorders and for treating contractures and inflammatory conditions that affect the muscular system.
PCT application WO 86/03681 A1 (26 Dec. 1984), relates generally to novel pharmaceutical compositions of matter comprising one or more non-steroidal anti-inflammatory drugs other than aspirin, acetaminophen and phenacetin, in combination with at least one skeletal muscle relaxant, and optionally xanthine or a xanthine derivative, such as caffeine, and to methods of using said compositions in the treatment of a variety of skeletal muscle disorders including skeletal muscle spasm, certain orthopedic conditions, disk syndromes, low back pain and the like.
United Kingdom patent application GB 2 197 198 A1 (Sandoz Ltd.) 3 Nov. 1986, describes to novel pharmaceutical preparations comprising ibuprofen and tizanidine with analgesic and myotonolytic activity as well as to methods of inducing analgesia and of treating conditions associated with increased muscle tone. The composition is preferably formulated as a tablet and desirably the weight ratio of tizanidine to ibuprofen is from 1:50 to 1:200, especially 1:100.
French patent FR 2 725 134 B1 (LABORATOIRES LEDERLE) 4 Oct. 1994, relates to a new pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof and thiocolchicoside or a pharmaceutically acceptable salt thereof in a ratio generally ranging between approximately 1:50 and approximately 1:200. According to this invention, the pharmaceutical composition is used in the treatment of the painful muscle syndromes and more particularly in the treatment of the acute lumbagos.
European patent EP 0 837 684 B1 (Sanofi-Synthelabo) 13 Jun. 1995, relates to pharmaceutical compositions containing, in solid form, a diclofenac salt and thiocolchicoside combined with at least one pharmaceutically acceptable carrier are provided for use in therapy.
PCT application WO 98/52545 A1 (THE BOOTS COMPANY PLC) 22 May 1997, relates to pharmaceutical compositions comprising a combination of flurbiprofen with a therapeutically effective amount of one or more active ingredients selected from an antihistamine, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, a centrally acting analgesic, a local anaesthetic, an antibacterial compound, an antiviral compound, an antibiotic compound, an antifungal compound, minerals and vitamins and/or a burn-masking amount of an agent which has a warming effect on the mucosa of the throat.
Also in this application, the treatment comprises the administration to a patient in need thereof of a pharmaceutical composition in the form of a masticable or suckable solid dosage form or a liquid or spray which releases the flurbiprofen and active ingredient(s) and/or burn-masking agent in the oral cavity so as to deliver the active components to the surface of the sore throat.
It is well known that drugs used in the same therapeutic area or even for treating the same indication cannot always be combined a priori with the expectation of at least additive therapeutic effects. The scientific literature is full of examples wherein compounds of different classes, which are used to treat the same indications, cannot be combined into safe and efficacious dosage forms thereby resulting in incompatible drug combinations. The reasons for this unexpected lack of compatibility are varied; however, it is often found that the incompatible drug combinations result in increased side effects, unwanted drug interactions or new side effects. More specifically, in the area of analgesia there are drug combinations that are contraindicated for some or all of these very same reasons.
Conventional analgesic and myorelaxant therapy generally involves administration of a pharmaceutical composition containing one or more different analgesic and muscle relaxant drugs. However, not all combinations of analgesic drugs and muscle relaxant drugs are more suitable, in terms of safety or efficacy, than the administration of a single product.
To date no pharmaceutical compositions or dosage forms comprising a combination of a flurbiprofen and a α-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist in particular tizanidine or thiocoichicoside, have been made.